Extension of Radiotherapy Research

放射治疗研究的延伸

• 批准号: 8711380
• 负责人: RAYMOND E MEYN
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711380
• 关键词: Acute; Advanced Malignant Neoplasm; Adverse effects; Blood Vessels; Cancer Model; Cetuximab; Clinical Trials; Clinical Trials Cooperative Group; Data; Development; Distant Metastasis; Dose; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family member; Fractionation; Funding; Funding Mechanisms; Future; Growth Factor Receptors; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Instruction; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Laboratory Finding; Locally Advanced Malignant Neoplasm; Malignant neoplasm of lung; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Neoplasms; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Outcome; Pathway interactions; Patients; Phase III Clinical Trials; Play; Process; Prognostic Factor; Radiation; Radiation Therapy Oncology Group; Radiation Tolerance; Radiation therapy; Radiotherapy Research; Reaction; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regimen; Relapse; Relative (related person); Research Personnel; Role; Schedule; Signal Pathway; Signal Transduction; Site; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Toxic effect; Translations; Up-Regulation; Work; Xenograft Model; base; bench to bedside; bioluminescence imaging; cancer cell; chemotherapy; experience; imaging modality; improved; in vivo; innovation; novel; overexpression; pre-clinical; research clinical testing; response; sound; therapy resistant; tumor; tumor growth; tumor xenograft

Innovations in radiation fractionation, planning, and delivery and development of combinations of radiation, with chemotherapy have improved the local-regional control (LRC) of advanced cancers of the upper aerodigestive track (UADT), including head & neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), resulting in better survival but at the expense of increased toxicity. Studies conducted through this project identified the epidermal growth factor receptor (EGFR) as an important determinant of cellular radiation sensitivity, elucidated mechanisms by which EGFR governs cellular response to radiation, and established the combination of radiation with cetuximab (monoclonal antibody against EGFR) as a novel, less toxic, frontline therapy for patients with locally advanced HNSCC. This represents a successful translation from the bench to bedside in merely a nine year time span. However, the results of the pivotal trial showed that there is room for further improvement in LRC and the impact on distant metastasis has been minimal. Emerging data show that high level of insulin-like growth factor receptor 1 (IGF-1 R) expression is associated with resistance to therapy and that crosstalk exists between EGFR and IGF-1 R pathways. We have generated preliminary preclinical evidence showing that cancer cells upregulate IGF-1 R in response to EGFR antagonists. These new findings led us to propose the following hypotheses: (1) constitutive or induced upregulation of IGF-1 R is a major mechanism for lack of enhancement of tumor response to radiation by EGFR antagonist alone and (2) co-targeting both EGFR and IGF-1 R signaling pathways, using their respective monoclonal antibodies cetuximab and A12, in conjunction with radiation will yield superior outcome than blockade of EGFR signaling alone. To test these hypotheses, we propose the following specific aims: 1) determine the direct radiosensitizing effect of A12 on HNSCCs and NSCLCs in vitro; 2) optimize the combination of fractionated radiotherapy with A12 using human tumor xenograft models; 3) assess the activity of A12 in suppressing invasion and metastatic spread using an bioluminescence imaging method; and 4) assess the effects of combination of radiation with cetuximab and A12. When encouraging, results will serve as the basis for formulating compelling regimen for clinical testing.

辐射分馏，计划和交付以及辐射组合的创新， 使用化学疗法改善了上层晚期癌症的局部区域对照（LRC） 机修器轨道（UADT），包括头部和颈部鳞状细胞癌（HNSCC）和非小细胞 肺癌（NSCLC），导致更好的生存率，但以毒性增加为代价。进行的研究 通过该项目，将表皮生长因子受体（EGFR）确定为重要的决定因素 细胞辐射敏感性，阐明EGFR控制辐射反应的机制， 并确定辐射与西妥昔单抗（对EGFR的单克隆抗体）的组合为A 针对患有局部晚期HNSCC患者的新型，毒性较小的前线治疗。这代表了成功 仅在九年的时间内从长凳上翻译到床边。但是，关键的结果 试验表明，LRC有进一步改善的空间，并且对遥远转移的影响 很少。新兴数据表明，高水平的胰岛素样生长因子受体1（IGF-1 R） 表达与对治疗的抗性有关，并且在EGFR和IGF-1之间存在串扰 途径。我们已经产生了初步的临床前证据，表明癌细胞上调IGF-1 R 响应EGFR拮抗剂。这些新发现使我们提出了以下假设：（1） 本构或诱导的IGF-1 R上调是缺乏肿瘤增强的主要机制 EGFR拮抗剂对辐射的响应，以及（2）共同靶向EGFR和IGF-1 R信号传导 使用各自的单克隆抗体西妥昔单抗和A12的途径与辐射结合 与仅封闭EGFR信号传导相比，产生较好的结果。为了检验这些假设，我们提出了 以下特定目的：1）确定A12对HNSCC和NSCLCS中A12的直接放射敏化作用 体外2）使用人肿瘤异种移植物优化分离放疗与A12的组合 模型； 3）使用A12评估A12的活性在抑制侵袭和转移扩散中使用 生物发光成像方法； 4）评估辐射与西妥昔单抗和 A12。鼓励时，结果将作为制定引人注目的临床方案的基础 测试。